Antibiotic Drugs; Cefpodoxime Proxetil, Cefpodoxime Proxetil Tablets, and Cefpodoxime Proxetil Granules for Oral Suspension

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 430, 436, and 442

[Docket No. 95N-0186]

Antibiotic Drugs; Cefpodoxime Proxetil, Cefpodoxime Proxetil

Tablets, and Cefpodoxime Proxetil Granules for Oral Suspension

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is amending the

antibiotic drug regulations to include accepted standards for a new

antibiotic drug, cefpodoxime proxetil, and its use in two dosage forms,

cefpodoxime proxetil tablets and cefpodoxime proxetil granules for oral

suspension. The manufacturer has supplied sufficient data and

information to establish its safety and efficacy.

DATES: Effective December 27, 1995; written comments, notice of

participation, and request for a hearing by December 27, 1995; data,

information, and analyses to justify a hearing by January 26, 1996.

ADDRESSES: Submit written comments to the Dockets Management Branch

(HFA-305), Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr.,

Rockville, MD 20857.

[[Page 58230]]

FOR FURTHER INFORMATION CONTACT: James Timper, Center for Drug

Evaluation and Research (HFD-520), Food and Drug Administration, 5600

Fishers Lane, Rockville, MD 20857, 301-443-6714.

SUPPLEMENTARY INFORMATION: FDA has evaluated data submitted in

accordance with regulations promulgated under section 507 of the

Federal Food, Drug, and Cosmetic Act (21 U.S.C. 357), as amended, with

respect to a request for approval of a new antibiotic drug, cefpodoxime

proxetil, and its use in two dosage forms, cefpodoxime proxetil tablets

and cefpodoxime proxetil granules for oral suspension. The agency has

concluded that the data supplied by the manufacturer concerning these

antibiotic drugs are adequate to establish their safety and efficacy

when used as directed in the labeling and that the regulations should

be amended in 21 CFR parts 430, 436, and 442 to include accepted

standards for these products.

Environmental Impact

The agency has determined under 21 CFR 25.24(c)(6) that this action

is of a type that does not individually or cumulatively have a

significant effect on the human environment. Therefore, neither an

environmental assessment nor an environmental impact statement is

required.

Submitting Comments and Filing Objections

This final rule announces standards that FDA has accepted in a

request for approval of an antibiotic drug. Because this final rule is

not controversial and because, when effective, it provides notice of

accepted standards, FDA finds that notice and comment procedure is

unnecessary and not in the public interest. This final rule, therefore,

is effective December 27, 1995. However, interested persons may, on or

before December 27, 1995, submit written comments to the Dockets

Management Branch (address above). Two copies of any comments are to be

submitted, except that individuals may submit one copy. Comments are to

be identified with the docket number found in brackets in the heading

of this document. Received comments may be seen in the Dockets

Management Branch between 9 a.m. and 4 p.m., Monday through Friday.

Any person who will be adversely affected by this final rule may

file objections to it and request a hearing. Reasonable grounds for the

hearing must be shown. Any person who decides to seek a hearing must

file (1) on or before December 27, 1995, a written notice of

participation and request for a hearing, and (2) on or before January

26, 1996, the data, information, and analyses on which the person

relies to justify a hearing, as specified in 21 CFR 314.300. A request

for a hearing may not rest upon mere allegations or denials, but must

set forth specific facts showing that there is a genuine and

substantial issue of fact that requires a hearing. If it conclusively

appears from the face of the data, information, and factual analyses in

the request for a hearing that no genuine and substantial issue of fact

precludes the action taken by this order, or if a request for a hearing

is not made in the required format or with the required analyses, the

Commissioner of Food and Drugs will enter summary judgment against the

person(s) who request(s) the hearing, making findings and conclusions

and denying a hearing. All submissions must be filed in three copies,

identified with the docket number appearing in the heading of this

document and filed with the Dockets Management Branch.

The procedures and requirements governing this order, a notice of

participation and request for a hearing, a submission of data,

information, and analyses to justify a hearing, other comments, and

grant or denial of a hearing are contained in 21 CFR 314.300.

All submissions under this order, except for data and information

prohibited from public disclosure under 21 U.S.C. 331(j) or 18 U.S.C.

1905, may be seen in the Dockets Management Branch (address above)

between 9 a.m. and 4 p.m., Monday through Friday.

List of Subjects

21 CFR Part 430

Administrative practice and procedure, Antibiotics.

21 CFR Parts 436 and 442

Antibiotics.

Therefore, under the Federal Food, Drug, and Cosmetic Act and

under authority delegated to the Commissioner of Food and Drugs, 21 CFR

parts 430, 436, and 442 are amended as follows:

PART 430--ANTIBIOTIC DRUGS; GENERAL

1. The authority citation for 21 CFR part 430 continues to read as

follows:

Authority: Secs. 201, 501, 502, 503, 505, 507, 701 of the

Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353,

355, 357, 371); secs. 215, 301, 351 of the Public Health Service Act

(42 U.S.C. 216, 241, 262).

2. Section 430.4 is amended by adding new paragraph (a)(70) to

read as follows:

Sec. 430.4 Definitions of antibiotic substances.

(a) * * *

(70) Cefpodoxime proxetil. Cefpodoxime proxetil is an antibiotic

substance having the chemical structure described by the following

name: ()-1-Hydroxyethyl(+)-(6R,7R)-7-[2-(2-amino-4-

thiazolyl)glyoxylamido]-3-(methoxymethyl)-8-oxo-5-thia-1-

azabicyclo[4.2.0]oct-2-ene-2-carboxylate,72-(Z)-(O-methyloxime),

isopropyl carbonate (ester).

* * * * *

3. Section 430.5 is amended by adding new paragraphs (a)(105) and

(b)(107) to read as follows:

Sec. 430.5 Definitions of master and working standards.

(a) * * *

(105) Cefpodoxime proxetil. The term ``cefpodoxime proxetil

master standard'' means a specific lot of the (R) isomer of cefpodoxime

proxetil that is designated by the Commissioner as the standard of

comparison in determining the potency of the cefpodoxime proxetil

working standard.

(b) * * *

(107) Cefpodoxime proxetil. The term ``cefpodoxime proxetil working

standard'' means a specific lot of a homogeneous preparation of

cefpodoxime proxetil.

4. Section 430.6 is amended by adding new paragraph (b)(107) to

read as follows:

Sec. 430.6 Definitions of the terms ``unit'' and ``microgram'' as

applied to antibiotic substances.

-* -* * * *

(b) * * *

(107) Cefpodoxime proxetil.- The term ``microgram'' applied to

cefpodoxime proxetil means the cefpodoxime (potency) contained in 1.304

micrograms of the cefpodoxime proxetil master standard when dried.

PART 436--TESTS AND METHODS OF ASSAY OF ANTIBIOTIC AND ANTIBIOTIC-

CONTAINING DRUGS

5. The authority citation for 21 CFR part 436 continues to read as

follows:

Authority: Sec. 507 of the Federal Food, Drug, and Cosmetic Act

(21 U.S.C. 357).

6. Section 436.215 is amended by alphabetically adding a new entry

to the table in paragraph (b) and by adding new paragraph (c)(19) to

read as follows:

Sec. 436.215 Dissolution test.

-* * * * *

[[Page 58231]]

(b) * * *

----------------------------------------------------------------------------------------------------------------

Dosage form Dissolution medium Rotation rate\1\ Sampling times(s) Apparatus

----------------------------------------------------------------------------------------------------------------

* * * * * *

*

Cefpodoxime proxetil tablets.... 900 mL pH 3.0 glycine 75 30 min............... 2

buffer.

* * * * * *

*

----------------------------------------------------------------------------------------------------------------

\1\ Rotation rate of basket or paddle stirring element (revolutions per minute).

(c) * * *

(19) Cefpodoxime proxetil--(i) Dissolution fluid: 0.04 molar

glycine buffer, pH 3.0--(A) Stock solution. Dissolve 54.5 grams of

glycine (aminoacetic acid) and 42.6 grams of sodium chloride in about

500 milliliters of deionized water in a 1-liter volumetric flask. Add

cautiously, and with swirling, 14.2 milliliters of concentrated

hydrochloric acid. Cool to room temperature. Dilute to volume with

deionized water and mix. Check the pH of the solution obtained by

diluting 50 milliliters of the stock solution to 900 milliliters with

deionized water. The pH should be 3.00.1. If necessary,

adjust the pH of the stock solution with 50 percent sodium hydroxide or

concentrated hydrochloric acid. Recheck that the pH of the working

solution is 3.00.1.

(B) Working solution. Dilute 50 milliliters of stock solution to

900 milliliters with deionized water.

(ii) Preparation of the working standard solutions. Accurately

weigh approximately 28 milligrams for the 100-milligram tablets and 56

milligrams for the 200-milligram tablets of the cefpodoxime proxetil

working standard and dissolve in 10 milliliters of methanol. Dilute to

200 milliliters with dissolution fluid. Prepare fresh daily.

(iii) Sample solutions. Filter the sample solutions through a

0.45-micron filter before use. Use the sample solution as it is removed

from the dissolution vessel without further dilution.

(iv) Procedure. Using a suitable spectrophotometer and water as

the blank, determine the absorbance of each standard and sample

solution at the absorbance peak at approximately 259 nanometers.

Determine the exact position of the absorption peak for the particular

instrument used.

(v) Calculations. Determine the percent of label dissolved as

follows:

Percent dissolved = (Asam/Astd) X (Cs/L) X V X P X

F1

where:

Asam = Absorbance of the sample at 259 nanometers;

Astd = Absorbance of the working standard solution at 259

nanometers;

Cs = Concentration of the working standard preparation in

milligrams per milliliter;

L = Tablet strength, in milligrams per tablet;

P = Purity of the reference standard in percent;

V = Volume of dissolution fluid used in milliliters (900); and

F1 = 0.7666 (conversion factor to free acid equivalents).

PART 442--CEPHA ANTIBIOTIC DRUGS

7. The authority citation for 21 CFR part 442 continues to read as

follows:

Authority: Sec. 507 of the Federal Food, Drug, and Cosmetic Act

(21 U.S.C. 357).

8. New Sec. 442.54 is added to subpart A to read as follows:

Sec. 442.54 Cefpodoxime proxetil.

(a) Requirements for certification--(1) Standards of identity,

strength, quality, and purity. Cefpodoxime proxetil is ()-

1-hydroxyethyl(+)-(6R,7R)-7-[2-(2-amino-4-thiazolyl)glyoxylamido]-3-

(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-

carboxylate,72-(Z)-(O-methyloxime), isopropyl carbonate (ester).

It is so purified and dried that:

(i) Its potency is not less than 690 micrograms and not more than

804 micrograms of cefpodoxime activity per milligram, on an anhydrous

basis.

(ii) The ratio of its R-epimer to total cefpodoxime is not less

than 0.5 and not more than 0.6.

(iii) Its moisture content is not more than 3 percent.

(iv) It gives a positive identity test.

(2) Labeling. It shall be labeled in accordance with the

requirements of Sec. 432.5 of this chapter.

(3) Requests for certification; samples. In addition to complying

with the requirements of Sec. 431.1 of this chapter, each such request

shall contain:

(i) Results of tests and assays on the batch for cefpodoxime

potency, isomer ratio, moisture, and identity.

(ii) Samples, if required by the Director, Center for Drug

Evaluation and Research: 10 packages, each containing approximately 500

milligrams.

(b) Tests and methods of assay--(1) Potency. Proceed as directed

in Sec. 436.216 of this chapter, using a suitable thermostatted column

heating mechanism to maintain a column temperature of 40 deg.C, an

ultraviolet detection system operating at a wavelength of 254

nanometers, a 15 centimeter X 4.6 millimeter (i.d.) column packed with

microparticulate (5 micrometers in diameter) reversed phase packing

material such as octadecyl silane bonded to silicas, a flow rate of 0.8

milliliter per minute, and a known injection volume of 2 microliters.

The retention time for the S-epimer is approximately 22 minutes and the

retention time for R-epimer is approximately 28 minutes. The internal

standard (propylparaben) has a retention time of 34 minutes. Mobile

phase, dilution solvent, resolution solution, internal standard

solution, working standard and sample solutions, system suitability

requirements, and calculations are as follows:

(i) Mobile phase. The mobile phase consists of 420 milliliters of

methanol, 580 milliliters of deionized water, and 230 milligrams of L-

histidine hydrochloride. The pH is adjusted to 2.50.1 using

2N sulfuric acid. The mobile phase must be at room temperature for a

correct pH measurement. The methanol concentration may be adjusted to

achieve comparable retention times from column to column. Increasing

methanol reduces retention times. Filter the mobile phase through a

suitable filter capable of removing particulate matter 0.5 micron in

diameter and degas it just before its introduction into the

chromatograph.

(ii) Dilution solvent. Prepare a solvent for dilution by

thoroughly mixing 495 milliliters of deionized water, 495 milliliters

of acetonitrile, and 10 milliliters of acetic acid in an appropriate

container.

(iii) Resolution solution. Prepare a 1 milligram per milliliter

solution of any bulk containing ANTI-A in dilution solvent. Use this

solution to determine the resolution between ANTI-A and the

[[Page 58232]]

later-eluting drug epimer (R-epimer). Alternately, the resolution

factor can be determined between the R and S isomers.

(iv) Internal standard solution. Prepare a solution of

propylparaben in dilution solvent at a concentration of 10 milligrams

per milliliter.

(v) Preparation of working standard solutions. Accurately weigh

approximately 42 milligrams of the cefpodoxime proxetil working

reference standard add 3 milliliters of internal standard solution and

25 milliliters of dilution solvent. The standard solution is stable for

at least 48 hours. Refrigeration is not recommended.

(vi) Sample solution. Accurately weigh approximately 42 milligrams

of the sample, add 3 milliliters of internal standard and 25

milliliters of dilution solvent. The sample solution is stable for at

least 48 hours. Refrigeration is not recommended.

(vii) System suitability requirements--(A) Asymmetry factor.The

asymmetry factor (As) is satisfactory if it is not less than 0.8

and not more than 1.1 for the R-epimer of cefpodoxime peak.

(B) Efficiency of the column. The absolute efficiency (hr)

is satisfactory if it is not more than 5 for the R-epimer peak.

(C) Resolution factor. The resolution factor (R) between the peak

for ANTI-A and the peak for the R-epimer is satisfactory if it is not

less than 1.3. Alternately, the resolution factor (R) between the peak

for the R-epimer and the peak for the S-epimer of cefpodoxime is not

less than 11.

(D) Coefficient of variation (Relative standard deviation). The

coefficient of variation (SR in percent of 5 replicate injections)

is satisfactory if it is not more than 2 percent.

(E) Capacity factor (k'). The capacity factor (k') for the R-epimer

of cefpodoxime is satisfactory if it is not less than 10.4 and not more

than 15.6.

(F) If the system suitability parameters in this paragraph

(b)(1)(iv) have been met, then proceed as described in Sec. 436.216(b)

of this chapter.

(viii) Calculations. Calculate the micrograms of cefpodoxime

proxetil per milligram of sample on an anhydrous basis as follows:

Ru X Ps X 100

Micrograms of cefpodoxime = -----------------------------------

proxetil per milligram Rs X Cu X (100-m)

where:

Ru = Ratio of cefpodoxime proxetil peaks area (sum of both

epimers) to the internal standard peak response in the sample

solution;

Rs = Ratio of cefpodoxime proxetil peaks area (sum of both

epimers) to the internal standard peak response in the working

standard solution;

Ps = Cefpodoxime proxetil activity of the working standard

solution in micrograms per milliliter;

Cu = Milligrams of sample per milliliter of sample solution;

and

m = Percent moisture content of the sample.

(2) Isomer ratio. Using the procedure described in paragraph

(b)(1) of this section, calculate the ratio of the R-epimer (Ab) to the

sum of the S-epimer and R-epimer (Aa and Ab), by the equation

Isomer Ratio = Ab/(Aa + Ab)

where:

Aa = Area of the early eluting S-epimer peak; and

Ab = Area of the late eluting R-epimer peak.

(3) Moisture. Proceed as directed in Sec. 436.201 of this chapter,

except use 30 milliliters of solvent C instead of 20 milliliters of

solvent A.

(4) Identity. Proceed as directed in Sec. 436.211 of this chapter,

using the mineral oil mull prepared as described in paragraph (b)(2) of

that section.

9. New Secs. 442.154, 442.154a, and 442.154b are added to subpart B

to read as follows:

Sec. 442.154 Cefpodoxime proxetil oral dosage forms.

Sec. 442.154a Cefpodoxime proxetil tablets.

(a) Requirements for certification--(1) Standards of identity,

strength, quality, and purity. Cefpodoxime proxetil tablets are

composed of cefpodoxime proxetil and one or more suitable and harmless

diluents, binders, lubricants, colorings, and coating substances. Each

tablet contains cefpodoxime proxetil equivalent to either 100

milligrams or 200 milligrams of cefpodoxime. Its cefpodoxime proxetil

content is satisfactory if it is not less than 90 percent and not more

than 110 percent of the number of milligrams of cefpodoxime that it is

represented to contain. Its loss on drying is not more than 5 percent.

It passes the dissolution test. It passes the identity test. The

cefpodoxime proxetil used conforms to the standards prescribed by

Sec. 442.54(a)(1).

(2) Labeling. It shall be labeled in accordance with the

requirements of Sec. 432.5 of this chapter.

(3) Requests for certification; samples. In addition to complying

with the requirements of Sec. 431.1 of this chapter, each such request

shall contain:

(i) Results of tests and assays on:

(A) The cefpodoxime proxetil used in making the batch for potency,

isomer ratio, moisture, and identity.

(B) The batch for content, loss on drying, dissolution, and

identity.

(ii) Samples, if required by the Director, Center for Drug

Evaluation and Research:

(A) The cefpodoxime proxetil used in making the batch: 10

packages, each containing approximately 500 milligrams.

(B) The batch: A minimum of 100 tablets.

(b) Tests and methods of assay--(1) Cefpodoxime content. Proceed as

directed in Sec. 442.54(b)(1), preparing the sample solution and

calculating the cefpodoxime content as follows:

(i) Preparation of sample solution. Obtain the average tablet

weight of at least 20 tablets. Grind the tablets using a mortar and

pestle. Weigh approximately 660 milligrams into a suitable container.

Add 30 milliliters of internal standard solution. Shake for 30 minutes

using a horizontal platform shaker or equivalent. Centrifuge for about

10 minutes at 3,000 revolutions per minute until the particulate matter

has settled. Withdraw a 1 milliliter aliquot of the supernatant and

dilute with 9 milliliters of dilution solvent. The sample solutions are

stable for at least 48 hours. Refrigeration is not recommended.

(ii) Calculations. Calculate the cefpodoxime content as follows:

Milligrams of cefpodoxime per tablet = (Rsam/Rstd) X (Wstd/Wsam) X (F1/F3) X F2 X F4 X P

[[Page 58233]]

where:

Rsam = Ratio of cefpodoxime proxetil peaks area (sum of both

epimers) to the internal standard peak area in the sample

preparation;

Rstd = Ratio of cefpodoxime proxetil peaks area (sum of both

epimers) to the internal standard peak area in the standard

preparation;

Wstd = Weight of cefpodoxime proxetil reference standard, in

milligrams;

Wsam = Weight of sample, in milligrams;

F1 = Volume of internal standard used in the sample

preparation, in milliliters;

F2 = 0.766; The ratio of molecular weight for free-acid

cefpodoxime over the molecular weight of cefpodoxime proxetil

(427.46/557.61);

F3 = Volume of internal standard used in the standard

preparation, in milliliters;

F4 = Average tablet weight, i.e., weight of tablets used in

sample preparation divided by the number of tablets; and

P = Purity of the cefpodoxime proxetil reference standard, expressed

as a decimal.

(2) Loss on drying. Proceed as directed in Sec. 436.200(a) of this

chapter, except dry the sample at a temperature of 80 deg.C and a

pressure of 5 millimeters of mercury or less for 16 hours.

(3) Dissolution test. Proceed as directed in Sec. 436.215 of this

chapter. The quantity Q (the amount of cefpodoxime activity dissolved)

is 70 percent within 30 minutes.

(4) Identity. Using the high-performance liquid chromatographic

procedure described in paragraph (b)(1) of this section, the retention

times for the peaks of the active ingredients must be within 2 percent

of the retention times for the peaks of the corresponding reference

standards.

Sec. 442.154b Cefpodoxime proxetil granules for oral suspension.

(a) Requirements for certification--(1) Standards of identity,

strength, quality, and purity. Cefpodoxime proxetil granules for oral

suspension is cefpodoxime proxetil and one or more suitable and

harmless preservatives, sweeteners, suspending agents, buffers, and

flavorings. When constituted as directed in the labeling, each

milliliter contains the equivalent of either 10 or 20 milligrams

cefpodoxime activity. Its cefpodoxime proxetil content is satisfactory

if it is not less than 90 percent and not more than 110 percent of the

number of milligrams of cefpodoxime that it is represented to contain.

Its loss on drying is not more than 0.5 percent. When constituted as

described in the labeling, the pH of the suspension is not less than 4

and not more than 5.5. It passes the identity test. The cefpodoxime

proxetil used conforms to the standards prescribed by

Sec. 442.54(a)(1).

(2) Labeling. It shall be labeled in accordance with the

requirements of Sec. 432.5 of this chapter.

(3) Requests for certification samples. In addition to complying

with the requirements of Sec. 431.1 of this chapter, each such request

shall contain:

(i) Results of tests and assays on:

(A) The cefpodoxime proxetil used in making the batch for potency,

isomer ratio, moisture, and identity.

(B) The batch for content, loss on drying, pH, and identity.

(ii) Samples, if required by the Director, Center for Drug

Evaluation and Research:

(A) The cefpodoxime proxetil used in making the batch: 10 packages,

each containing approximately 500 milligrams.

(B) The batch: A minimum of 10 intermediate containers.

(b) Tests and methods of assay--(1) Cefpodoxime content. Proceed

as directed in Sec. 442.54(b)(1), preparing the sample solution and

calculating the cefpodoxime content as follows:

(i) Preparation of sample solution. Reconstitute as directed in

the labeling. Immediately before sampling the suspension, shake

vigorously for several seconds. Into a suitable container, accurately

weigh out 6 grams of the 50 milligrams per 5 milliliters suspension, or

3 grams of the 100 milligrams per 5 milliliters suspension. Add 5

milliliters of internal standard solution and 25 milliliters of

dilution solvent. Shake for 30 minutes using a horizontal platform

shaker or equivalent. Centrifuge for about 10 minutes at 3,000

revolutions per minute until the particulate matter has settled.

Withdraw a 1 milliliter aliquot of the supernatant and dilute with 1

milliliter of dilution solvent. The sample solutions are stable for at

least 48 hours. Refrigeration is not recommended.

(ii) Calculations. Calculate the cefpodoxime content as follows:

Milligrams of cefpodoxime per 5 milliliters of

suspension = (Rsam/Rstd) X (Wstd/Wsam) X (F1/F3) X (F2/F4) X F5 X P

where:

Rsam = Ratio of cefpodoxime proxetil peaks area (sum of both

epimers) to the internal standard peak area in the sample

preparation;

Rstd = Ratio of cefpodoxime proxetil peaks area (sum of both

epimers) to the internal standard peak area in the standard

preparation;

Wstd = Weight of cefpodoxime proxetil reference standard, in

milligrams;

Wsam = Weight of sample, in grams;

F1 = Volume of internal standard used in the sample;

preparation, in milliliters;

F2 = 0.766; The ratio of molecular weight for free-acid

cefpodoxime over the molecular weight of cefpodoxime proxetil

(427.46/557.61);

F3 = Volume of internal standard used in the standard

preparation, in milliliters;

F4 = 0.2; Factor to convert to 5 milliliters;

F5 = Specific gravity of suspension for milligram per 5

milliliter calculated on the air-free basis (specific gravity is

determined on a sample of suspension that has been shaken gently on

a platform shaker under vacuum for 2 hours); and

P = Purity of the cefpodoxime proxetil reference standard, expressed

as a decimal.

(2) Loss on drying. Proceed as directed in Sec. 436.200(a) of

this chapter, except dry the sample at a temperature of 80 deg.C and a

pressure of 5 millimeters of mercury or less for 16 hours.

(3) pH. Proceed as directed in Sec. 436.202 of this chapter,

using the drug constituted as directed in the labeling.

[[Page 58234]]

(4) Identity. Using the high-performance liquid chromatographic

procedure described in paragraph (b)(1) of this section, the retention

times for the peaks of the active ingredients must be within 2 percent

of the retention times for the peaks of the corresponding reference

standards.

Dated: November 13, 1995.

Murray M. Lumpkin,

Deputy Director, Center for Drug Evaluation and Research.

[FR Doc. 95-28893 Filed 11-24-95; 8:45 am]

BILLING CODE 4160-01-F